Pseudomonas aeruginosa Evasion of Phagocytosis Is Mediated by Loss of Swimming Motility and Is Independent of Flagellum Expression
Pseudomonas aeruginosa Evasion of Phagocytosis Is Mediated by Loss of Swimming Motility and Is Independent of Flagellum Expression
复制标题
DOI：
10.1128/iai.00144-10
复制
发表时间：
2010-07-01
影响因子：
3.1
通讯作者：
Berwin, Brent
中科院分区：
文献类型：
--
作者：
Amiel, Eyal;Lovewell, Rustin R.;Berwin, Brent
铜绿假单胞菌是一种致病性革兰氏阴性细菌，在免疫功能低下的个体中引起严重的机会性感染；特别是，铜绿假单胞菌感染的严重程度与囊性纤维化（CF）患者的不良预后呈正相关。由这种病原体建立的慢性感染与鞭毛表达下调和其他调节铜绿假单胞菌运动的基因有关。目前的范式是鞭毛表达的缺失使得细菌免疫逃避，这是由于识别鞭毛成分的吞噬受体的参与缺失和鞭毛蛋白介导的toll样受体（TLR）信号的免疫激活缺失。在这项工作中，我们采用细菌和哺乳动物遗传方法来证明运动能力的丧失，而不是鞭毛本身的丧失，是铜绿假单胞菌对吞噬作用产生抗性的关键因素。我们证明了等基因铜绿假单胞菌鞭毛功能缺陷，但保留完整的鞭毛，对小鼠和人类吞噬细胞的吞噬具有高度的抵抗力，其水平与鞭毛缺陷突变体相当。此外，我们发现小鼠吞噬细胞中MyD88信号的缺失并不能重现在鞭毛缺陷或动力缺陷的铜绿假单胞菌突变体中观察到的吞噬缺陷。我们的数据表明，细菌运动能力的丧失赋予了对吞噬的显著抵抗，这是独立于鞭毛表达和TLR信号。这些发现为临床铜绿假单胞菌分离株无运动性的充分记录观察以及这种表型如何赋予细菌在免疫逃避背景下的优势提供了解释。
Pseudomonas aeruginosa is a pathogenic Gram-negative bacterium that causes severe opportunistic infections in immunocompromised individuals; in particular, severity of infection with P. aeruginosa positively correlates with poor prognosis in cystic fibrosis (CF) patients. Establishment of chronic infection by this pathogen is associated with downregulation of flagellar expression and of other genes that regulate P. aeruginosa motility. The current paradigm is that loss of flagellar expression enables immune evasion by the bacteria due to loss of engagement by phagocytic receptors that recognize flagellar components and loss of immune activation through flagellin-mediated Toll-like receptor (TLR) signaling. In this work, we employ bacterial and mammalian genetic approaches to demonstrate that loss of motility, not the loss of the flagellum per se, is the critical factor in the development of resistance to phagocytosis by P. aeruginosa. We demonstrate that isogenic P. aeruginosa mutants deficient in flagellar function, but retaining an intact flagellum, are highly resistant to phagocytosis by both murine and human phagocytic cells at levels comparable to those of flagellum-deficient mutants. Furthermore, we show that loss of MyD88 signaling in murine phagocytes does not recapitulate the phagocytic deficit observed for either flagellum-deficient or motility-deficient P. aeruginosa mutants. Our data demonstrate that loss of bacterial motility confers a dramatic resistance to phagocytosis that is independent of both flagellar expression and TLR signaling. These findings provide an explanation for the well-documented observation of nonmotility in clinical P. aeruginosa isolates and for how this phenotype confers upon the bacteria an advantage in the context of immune evasion.